FEVERFEW: Tanacetum parthenium

Feverfew (Tanacetum parthenium) has gained popularity in the past decade for a time-honored use -- a pain-reliever for the treatment of migraine headache. Recent scientific research has resulted in new interest in the plant, given successful clinical trials in which the plant has been efficaciously used to provide symptomatic relief in migraine, a troubling condition that often does not respond to modern treatment methods.

Botany and Nomenclature

A member of the aster family (Asteraceae or Compositae), Feverfew is a strongly aromatic perennial originating from mountain scrub and rocky soil of the Balkan peninsula. For centuries it has been cultivated as a medicinal plant as well as an ornamental in Europe, and is now naturalized in hedges and waste places throughout much of Europe. The plant is naturalized in both North and South America.

It appears to have escaped from cultivation and become naturalized in the United States in the mid-nineteenth century. It is absent from the first edition of Asa Gray's Manual of Botany (1848), but by the time the 1870 edition of his Field Forest, and Garden Botany was published, Gray observed that it is "cultivated in old gardens, and [is] running wild."

Feverfew is naturalized in waste places, roadsides, and borders of woods from Quebec south to Maryland, west to Missouri, and Ohio (Fernald, 1950).

Botanically, the plant is best known in the modern literature as Tanacetum parthenium (L.) Schultz Bip. Other botanical names by which it has previously been known include Chrysanthemum parthenium (L.) Bernh., Leucanthemum parthenium (L.) Gren. & Gordon, and Pyrethrum parthenium (L.) Sm. The Swedish botanist Linnaeus referred to it as Matricaria parthenium.

Unfortunately, the names Tanacetum parthenium and Chrysanthemum parthenium were both noted as valid botanical names in seminal taxonomic reference works published in 1976. The former appeared in Volume 4 of Flora Europaea (Heywood in Tutin et al. eds., 1976) and the latter in Hortus Third (L.H. Bailey Hortorium, 1976). According to Tucker (1986), if the genus Chrysanthemum is defined sensu stricto (in the strictest or narrowest sense) -- as is done by Heywood -- then the genus includes only five annual species of the Mediterranean and Eurasia. If Chrysanthemum is interpreted sensu lato (in the broadest sense) -- as is done in Hortus Third -- then it would include upwards of 200 species. It is the inclination of modern taxonomists to separate the genus Chrysanthemum into several genera in the aster family. Here the "splitters" win over the "lumpers." Consequently, most perennial species formerly included in the genus Chrysanthemum are now referred to separate genera including Dendranthema (the "chrysanthemums" of horticulture), Balsamita, Leucanthemum and Tanacetum (Mabberly, 1987).

Feverfew received the name Tanacetum parthenium from C.H. Schultz (Schultz Bipontinus, 1805-1867) in an 1844 German monograph on the genus Tanacetum.

The generic name Tanacetum is derived from an altered form of athanasis (athanatos) meaning immortal, in allusion to the ever-lasting nature of the dried flowers. The specific name "parthenium" is derived from the Greek parthenos, virgin, which was originally applied to another plant by Hippocrates, referring to traditional use by women to help relieve menstrual cramps (Nicholson, 1886-87). This is an instance where botanical nomenclature has failed to provide a single unambiguous name for a well-defined species. However, most of us can at least agree on the English common name, feverfew, deriving from the Latin febrifuga, a febrifuge, referring to the plant's traditional role in lowering fevers.

History

In 1655 when John Goodyer produced the first English translation of the materia medica of Dioscorides (the first century Greek physician), eleven different Latin names were given for feverfew. Dioscorides mentioned use, as Goodyer puts it, for "melancholicall," which can be interpreted as used for headaches (Gunther, 1934). In the 1633 edition of Gerard's Herbal, Thomas Johnson, notes that "feverfew dried and made into pouder, and two drams of it taken with honie or sweet wine, purgeth by siege melancholy and flegme, whereforre it is very good for them that are giddie in the head, or which have the turning called Vertigo, this is a swimming and turning in the head. Also it is good for such as be melancholike, sad, pensive, and without speech" (Johnson, 1633, p. 653).

Culpepper (1787 ed.) also observes efficacy for headache, "It is very effectual for all pains in the head coming of a cold cause, the herb being bruised and applied to the crown of the head; as also for the Vertigo, that is a sunning or swimming of the head" (p. 150).

Throughout the eighteenth and nineteenth centuries, references to the plant were only passing. William Cullen considered the plant more active than wormwood (Artemisia absinthium), but admits, "I have seldom had such opportunity of seeing it employed as to enable me to determine precisely concerning its virtues" (Cullen, 1808, Vol 2, p. 209). It is absent from most of the major pharmacopoeias and only briefly mentioned in dispensatories. It was once the official "Herba Matricariae" of Germany, where it was commonly known as Mutterkraut. The 1849 Dispensatory of the United States only affords it "useful tonic properties," and admits it is little employed (Wood and Bache, 1849).

Prior to the last decade, twentieth century use of the plant had been relegated to folk medicine and popular herbals. Joseph Meyer (1917) lists its properties as tonic, carminative, emmenagogue, vermifuge and stimulant. Primary uses have included fevers, menstrual regulation, or external application as an anodyne (pain-reliever), Naturalized in South and Central America, the Kallaway of the Andes, use feverfew or Santa Maria, as it is also known, to promote the functional activity of the stomach, for colic, stomachache, morning sickness and kidney pains. One twig of the plant is steeped in a cup of boiling water and drunk once a day (Bastien, 1987). In Costa Rica, a decoction has been used for cardioactive, digestive and emmenagogue properties, as well as an enema for worms. Mexicans have used it as a sitz bath to regulate menstruation as well as an antispasmodic and tonic. Venezuelans have used the plant decoction for the treatment of earache (Duke, 1985).

Modern Use

Modern interest has primarily focused on the use of feverfew in the prophylaxis of migraine. Parthenolide is regarded as the primary chemical constituent responsible for the activity of feverfew in the prevention of migraines. It was first isolated by Sorm and coworkers (Soucek, Herout and Sorm, 1959) who assigned the wrong structure to it. Govindachari (1964) isolated the same compound and deduced the correct structure from the roots of champaca (Michelia champaca), an evergreen member of the magnolia family from the Himalayas. This chemical, a sesquiterpene lactone, is found in at least thirty-four plant species, including some forms of common tansy (Tanacetum vulgare). Bohlmann and Zdero (1982) identified thirty-nine constituents of feverfew, including parthenolide (D. Awang, personal communication, 1991).

Correctly-identified whole dried leaf, (with at least 0.2 percent parthenolide), has been proposed by Canadian regulatory authorities as a minimum standard for reasonable certainty of claims in feverfew products. French authorities have proposed a level of 0.1 percent (of leaf and stem). The feverfew used in two published clinical trials on the effects of feverfew is comparable to the Canadian standard. The parthenolide content of various sources of feverfew has been found to be highly variable (Awang, 1987, 1989a, 1989b, 1990, Awang, et al., 1991; Heptinstall, et al., 1992). While North American feverfew leaf products were found to contain less than 0.1% parthenolide, Awang et al. (1991) found that a double-flowered form T. parthenium form flosculosum, contained 1.27% parthenolide. Future product development, therefore, may focus on identifying plant material with consistently high levels of parthenolide.

Health and Welfare Canada has issued a DIN (Drug Identification Number) to a feverfew product manufactured in England. This is an important regulatory development, as it is the first DIN issued to an herbal product which allows substantive claims for a relatively significant medical condition. While some valerian products, for example, can claim they may help as a sleep aid, the new feverfew product will be allowed to carry the claim "used as a prophylactic against migraines." The product will be required to be standardized to contain 0.2% parthenolide (Awang, 1994).

Research has been conducted to elucidate the mechanisms of feverfew actions. Parthenolide, and perhaps other sesquiterpene lactones, have been shown to reduce the secretory activity of blood platelets and white blood cells in laboratory studies, providing a possible basis for feverfew's effectiveness in migraine, arthritis, and psoriasis.

Abnormal platelet behavior has been implicated as a possible explanation for the development of migraines. Platelets release the hormone serotonin (also referred to as 5-HT) during a migraine attack. Serotonin constricts blood vessels among other actions. Serotonin antagonists have been suggested for use in a supportive role in migraine prevention. Feverfew have has been shown (in vitro) to inhibit serotonin release from platelets (Murphy, Heptinstall and Mitchell, 1988). The effectiveness of various feverfew preparations in inhibiting the release of serotonin from human blood platelets has been found to correlate well with parthenolide content in freeze-dried or air-dried whole feverfew leaf (Heptinstall et al., 1992).

In the past decade interest in clinical studies on feverfew resulted from a national newspaper article in England in which 25,000 replies were received in response to a request for personal experience on the benefit of feverfew in allaying the symptoms of migraine (Anon., 1989). A preliminary broad-based clinical study by E. Stewart Johnson in the UK was conducted to evaluate the effect of feverfew on 300 migraine suffers who had been taking feverfew for about 2.5 years. According to the report published in the British medical publication Mims Magazine, 70 percent of those migraine sufferers interviewed claimed to have experienced a reduction in frequency and/or pain from migraine since they had used the herb. Three small fresh leaves or one large fresh leaf were consumed each day. Many involved in the study had previously failed to respond to orthodox medical treatment (Johnson, 1983; as reviewed by Warren, 1986). This preliminary clinical trial stimulated additional studies.

A 1985 study by Johnson et al. on the efficacy of feverfew for the prophylactic treatment of migraine was conducted at the City of London Migraine Clinic in collaboration with the Chelsea College of the University of London. The seventeen patients involved in the double-blind study had all eaten the leaves of feverfew for at least three months before commencement of the study. Before the test, the average daily dose of fresh leaves ingested by the patients was sixty mg. per day. During the study, patients were given twenty-five mg. of freeze-dried leaf capsules. Nine of the patients received placebo, and experienced an increase in the frequency and severity of headache, nausea, and vomiting. Those who took the feverfew experienced no change in the frequency or severity of migraine symptoms, prompting the researchers to conclude that feverfew is efficacious in the preventative treatment of migraine (Johnson et al., 1985; Awang, 1989a, 1993; Hobbs, 1989). The study has been criticized on the basis of self selection, since patients had been self-medicating with feverfew products prior to the trail.

Murphy, Heptinstall and Mitchell (1988) reported on the results of a randomized, double-blind, placebo-controlled, cross-over trial of feverfew in migraine prevention conducted at the University Hospital, Nottingham. Following a one-month single-blind run-in period, seventy-two volunteers were randomly selected to receive either one capsule of feverfew daily or a matching placebo (dried cabbage leaves) for a four month period. One hard capsule of dried leaves, with weights ranging from 40-114 mg., was judged to correspond to two medium-sized leaves. At the completion of the study full information was available for fifty-nine participants. According to the authors, the feverfew treatment was clearly associated with a reduction in both frequency of migraine headaches and vomiting associated with the attacks. There was also a minor trend towards a reduction in the severity of migraines. However, there was no significant effect in limiting the duration of migraine attacks compared with the placebo. No adverse reactions were recorded in the study, though the authors note the need for longer term safety studies given the fact that lifelong treatment may be necessary for migraine sufferers.

While no long-term studies have beer done on safety, minor ulceration of the oral mucosa was reported in twelve percent of the patients in the study by Johnson et al. (1985). A relatively small number (seven percent) of patients chewing the fresh leaves have experienced oral mucosa and tongue inflammation, accompanied by swelling of the lips, and occasional loss of taste which prevented continued use of the plant (Awang, 1989a).

Based on previous reports of anti-inflammatory activity of feverfew, Pattrick, Heptinstall, and Doherty (1989) conducted a double-blind, placebo controlled, randomized study on the effect of the dried chopped leaves (70-86mg.) in the treatment of rheumatoid arthritis. Over the six week trial, forty-one female patients with symptomatic rheumatoid arthritis received feverfew or placebo. Over thirteen laboratory and/or clinical parameters were assessed. The authors concluded that there were no important differences between the control group and those receiving feverfew. Therefore, oral dosage did not seem to be of any benefit in the treatment of rheumatoid arthritis. However, those patients participating in the study had "inadequately controlled inflammatory joint symptoms" from the outset, and were already being considered for a change of treatment. In other words, they were not responding well to the treatment they had previously received before the feverfew study began. The authors note that the results do not preclude possible benefits for the use of feverfew in osteoarthritis and soft tissue lesions "for which self treatment with feverfew is probably most common."

Summary

Feverfew (Tanacetum parthenium) has been recorded as a potential treatment for fevers and headaches for about 2000 years. Long grown in herb gardens of Europe, and naturalized in North and South America, the plant has had a long reputation of folk use for the treatment of headaches. Over the past 15 years pharmacological, chemical, and clinical studies have confirmed the value of the use of feverfew in the symptomatic relief of migraine symptoms. Further studies are necessary to determine long-term safety, and the optimum form, duration, composition, and quality control of feverfew products, along with possible utility in inflammatory joint diseases and psoriasis. Ironically, given the fact that the name feverfew derives from its historical use to lower fevers, it is surprising that the plant has not been studied for fever-reducing activity. For more detailed information on feverfew see the excellent review articles by Awang (1989a and 1993) and Hobbs (1989).